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Abstract Sorghum ratooning, a time and labor-saving cultivation practice, is increasingly being adopted by farmers in Southwest China as an alternative. Efficient N fertilizer management is critical for economical production of sorghum and the long-term protection of the environment. To investigate the impact of N management on grain yield and nitrogen use efficiencies (NUEs) of ratoon sorghum system, a three-year field experiment was conducted for Jinyunuo3 (a hybrid cultivar) and Guojiaohong1 (an inbred cultivar) using 12 combinations of N rates and splitting ratios. The results showed that increasing N rate and splitting application times led to improvements in various growth parameters such as dry matter weight, crop growth rate (CGR), leaf area index (LAI), and photosynthetic potential (PP). The main, ratoon, and annual yields increased with N rate increase, but there was no significant difference between 225 and 150 kg N ha−1 in the ratoon and annual yields. Splitting the application of N fertilizer enhanced grain yield compared to a single dose application method, especially three-split applications yielded higher than two-split applications. Compared with N rates of 225 and 150 kg ha−1, N rate of 75 kg ha−1 increased apparent recovery rate of applied nitrogen (REN), agronomic efficiency of applied nitrogen (AEN), and partial factor productivity from applied nitrogen (PFPN) in both main season and whole year. But through splitting application methods at high N rates could achieve similar or even higher levels of NUEs compared to all applied as basal fertilizer at low N rates. Therefore, it could be recommended that applying 150 kg N ha−1 with a basal-jointing-heading fertilizer ratio of 2:4:4 represented an efficient N management practice to synchronously obtain high grain yield and NUEs in ratoon sorghum system in Southwest China.

ObjectiveDeveloping and validating a clinical prediction nomogram of 28-day mortality in critically ill patients with acute gastrointestinal injury (AGI).MethodsFirstly, the construction of a clinical prediction model was developed using data obtained from a prospective observational study from May 2023 to April 2024. Then, data from a prospective multicenter observational study conducted in the intensive care units of 12 teaching hospitals in 2014 were utilized to independently and externally validate the clinical prediction model developed in the first part. We first screened the covariates of the development cohort by univariate cox regression, and then carried out cox regression analysis on the development cohort by backward stepwise regression to determine the optimal fitting model. Subsequently, a nomogram was derived from this model.ResultsA total of 1102 and 379 patients, 28-day mortality occurred in 20.3% and 15.8% of patients respectively, were included in the development and validation cohort, respectively. We developed a nomogram in critically ill patients with AGI and the AGI grade, APACHE II score, Mechanical ventilation (MV), Feeding intolerance (FI) and daily calorie intake (DCI) in 72 h, were independent predictors of 28-day mortality, with the OR of the AGI grade was 1.910 (95% CI, 1.588–2.298; P < 0.001), the OR of APACHE II score was 1.099 (95% CI, 1.069–1.130; P < 0.001), the OR of MV was 1.880 (95% CI, 1.215–2.911; P = 0.005), the OR of FI was 3.453 (95% CI, 2.414–4.939; P < 0.001) and the DCI > 0.7 or < 0.5 of calorie target is associated with increased 28-day mortality, with OR of 1.566 (95% CI, 1.024–2.395; P = 0.039) and 1.769 (95% CI, 1.170–2.674; P = 0.007), respectively. Independent external validation of the prediction model was performed. This model has good discrimination and calibration. The DCA and CIC also validated the good clinical utility of the nomogram.ConclusionThe prediction of 28-day mortality can be conveniently facilitated by the nomogram that integrates AGI grade, APACHE II score, MV, FI and DCI in 72 h in critically ill patients with AGI.

Abstract Purpose This comprehensive investigation delved into the intricate causal interplay existing between cardiovascular-related plasma proteins and the susceptibility to colorectal cancer, leveraging the robust framework of Mendelian randomization, and employed expression profiling and survival analysis to unravel the latent clinical worth embedded within pertinent gene expressions. Methods Protein quantitative trait loci (pQTLs) of 85 cardiovascular proteins were employed as instrumental variables to investigate the causal relationship between proteins and CRC risk using a Mendelian randomization approach. Causal inferences were graded as strong, intermediate or weak based on statistical checks. Drug-target MR examined VEGF receptors for their potential as therapeutic targets for colorectal cancer. Differential expression analysis, diagnostic ROC curves, and survival analyses were performed for identified proteins using RNA-seq data from The Cancer Genome Atlas (TCGA) colorectal cancer cohort. Results Using cis-pQTLs, LOX-1, VEGF-A and OPG were associated with increased CRC risk (strong evidence), while PTX3, TNF-R2 and MMP-7 were protective (strong evidence). Pan-pQTL analysis found MMP-10 increased risk (intermediate evidence) and ADM increased risk (weak evidence). Drug-target MR found VEGF R1 may be promising therapeutic targets. Differential expression analysis revealed seven genes encoding the identified proteins were dysregulated in tumors. ROC analysis showed five gene expression had high diagnostic accuracy. KM analysis showed four genes had prognostic value. Conclusions This large-scale MR study implicates several cardiovascular proteins in CRC susceptibility and progression. Findings highlight roles for VEGF signaling and extracellular matrix regulation. Results nominate specific proteins as potential diagnostic biomarkers or therapeutic targets warranting further investigation.

Abstract Background Human hematopoietic organoids have a wide application value for modeling human bone marrow diseases, such as acute hematopoietic radiation injury. However, the manufacturing of human hematopoietic organoids is an unaddressed challenge because of the complexity of hematopoietic tissues. Methods To manufacture hematopoietic organoids, we obtained CD34+ hematopoietic stem and progenitor cells (HSPCs) from human embryonic stem cells (hESCs) using stepwise induction and immunomagnetic bead-sorting. We then mixed these CD34+ HSPCs with niche-related cells in Gelatin-methacryloyl (GelMA) to form a three-dimensional (3D) hematopoietic organoid. Additionally, we investigated the effects of radiation damage and response to granulocyte colony-stimulating factor (G-CSF) in hematopoietic organoids. Results The GelMA hydrogel maintained the undifferentiated state of hESCs-derived HSPCs by reducing intracellular reactive oxygen species (ROS) levels. The established hematopoietic organoids in GelMA with niche-related cells were composed of HSPCs and multilineage blood cells and demonstrated the adherence of hematopoietic cells to niche cells. Notably, these hematopoietic organoids exhibited radiation-induced hematopoietic cell injury effect, including increased intracellular ROS levels, γ-H2AX positive cell percentages, and hematopoietic cell apoptosis percentages. Moreover, G-CSF supplementation in the culture medium significantly improved the survival of HSPCs and enhanced myeloid cell regeneration in these hematopoietic organoids after radiation. Conclusions These findings substantiate the successful manufacture of a preliminary 3D hematopoietic organoid from hESCs-derived HSPCs, which was utilized for modeling hematopoietic radiation injury and assessing the radiation-mitigating effects of G-CSF in vitro. Our study provides opportunities to further aid in the standard and scalable production of hematopoietic organoids for disease modeling and drug testing.

Abstract This study aimed to explore the changes of pharmacokinetic parameters after meropenem in patients with abdominal septic shock after gastrointestinal perforation, and to simulate the probability of different dosing regimens achieving different pharmacodynamic goals. The study included 12 patients, and utilized high performance liquid chromatography-tandem mass spectrometry to monitor the plasma concentration of meropenem. The probability of target attainment (PTA) for different minimum inhibitory concentration (MIC) values and %fT > 4MIC was compared among simulated dosing regimens. The results showed that in 96 blood samples from 12 patients, the clearance (CL) of meropenem in the normal and abnormal creatinine clearance subgroups were 7.7 ± 1.8 and 4.4 ± 1.1 L/h, respectively, and the apparent volume of distribution (Vd) was 22.6 ± 5.1 and 17.2 ± 5.8 L, respectively. 2. Regardless of the subgroup, 0.5 g/q6h infusion over 6 h regimen achieved a PTA > 90% when MIC ≤ 0.5 mg/L. 1.0 g/q6h infusion regimen compared with other regimen, in most cases, the probability of making PTA > 90% is higher. For patients at low MIC, 0.5 g/q6h infusion over 6 h may be preferable. For patients at high MIC, a dose regimen of 1.0 g/q6 h infusion over 6 h may be preferable. Further research is needed to confirm this exploratory result.

Abstract There have been reports of long coronavirus disease (long COVID) and breakthrough infections (BTIs); however, the mechanisms and pathological features of long COVID after Omicron BTIs remain unclear. Assessing long-term effects of COVID-19 and immune recovery after Omicron BTIs is crucial for understanding the disease and managing new-generation vaccines. Here, we followed up mild BA.2 BTI convalescents for six-month with routine blood tests, proteomic analysis and single-cell RNA sequencing (scRNA-seq). We found that major organs exhibited ephemeral dysfunction and recovered to normal in approximately six-month after BA.2 BTI. We also observed durable and potent levels of neutralizing antibodies against major circulating sub-variants, indicating that hybrid humoral immunity stays active. However, platelets may take longer to recover based on proteomic analyses, which also shows coagulation disorder and an imbalance between anti-pathogen immunity and metabolism six-month after BA.2 BTI. The immunity-metabolism imbalance was then confirmed with retrospective analysis of abnormal levels of hormones, low blood glucose level and coagulation profile. The long-term malfunctional coagulation and imbalance in the material metabolism and immunity may contribute to the development of long COVID and act as useful indicator for assessing recovery and the long-term impacts after Omicron sub-variant BTIs.

Summary: Background: Omicron sub-variants breakthrough infections (BTIs) have led to millions of coronavirus disease 2019 (COVID-19) cases worldwide. The acute-phase immune status is critical for prognosis, however, the dynamic immune profiling of COVID-19 during the first month after BTIs remains unclear. Methods: In this study, we monitored the immune dynamics at various timepoints in a longitudinal cohort during the first month post-BTIs through clinical evaluation, single-cell RNA sequencing (scRNA-seq), T cell receptor (TCR)/B cell receptor (BCR) sequencing, and antibody mass spectrometry. Findings: Serological analysis revealed limited impairment to functions of major organs, active cellular and humoral immunity at 2 weeks post-BTI, with significant increases in cytokines (CKs) and neutralizing antibody levels. However, 1 month post-BTI, organ function parameters and CK levels reverted to pre-infection levels, whereas neutralizing antibody levels remained high. Notably, scRNA-seq showed that lymphocytes maintained strong antiviral activity and cell depletion at 2 weeks and 1 month post-BTI, with genes CD81, ABHD17A, CXCR4, DUSP1, etc. upregulated, and genes PFDN5, DYNLRB1, CD52, etc. downregulated, indicating that lymphocytes status take longer to recover to normal levels than that routine blood tests revealed. Additionally, T cell-exhaustion associated genes, including LAG3, TIGIT, PDCD1, CTLA4, HAVCR2, and TOX, were upregulated after BTI. TCRs and BCRs exhibited higher clonotypes, mainly in CD8Tem or plasmablast cells, at 2 weeks post-BTI comparing 1 month. More IgG and IgA-type BCRs were found in the groups of 1 month post-BTI, with higher somatic hypermutation, indicating greater maturity. Verification of monoclonal antibodies corresponding to amplified BCRs highlighted the antigen-specific and broad-spectrum characteristics. Interpretation: Our study elucidated the dynamic immune profiling of individuals after Omicron BA.5 sublineages BTI. Strong immune activation, antiviral response, antibody maturation and class transition at 2 weeks and 1 month after BTI may provide essential insights into pathogenicity, sequential immune status, recovery mechanisms of Omicron sublineage BTI. Funding: This study was supported by the National Key R&D Program of China, the China Postdoctoral Science Foundation, Guangdong Basic and Applied Basic Research Foundation, the National Natural Science Foundation of China, CAS Project for Young Scientists in Basic Research, and the Air Force Special Medical Center Science and Technology Booster Program.

The highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) poses a significant threat to the global swine industry. Vaccination is a preventive measure against viral infections. However, the use of vaccines in livestock healthcare programs faces the challenge of safety and delayed immune responses. Earlier studies have shown the potential of modified Bazhen powder as an immunomodulator with significant biological properties, but its effect on vaccines against HP-PRRSV is yet to be studied. This study elucidated how modified Bazhen powder could improve the safety and efficacy of the conventional PRRSV vaccine by evaluating T-cell responses, antibody levels, clinical symptoms, levels of viremia, organ health, and cytokine production. The results revealed that the oral application of modified Bazhen powder in combination with PRRS vaccination improved both cellular and humoral immunity, accelerated viremia clearance, improved lung injury scores, and reduced viral load in the tonsils. The modified Bazhen powder also effectively reduced inflammatory responses following a PRRSV challenge. These findings further highlight the pharmacological properties of modified Bazhen powder as a potential oral immunomodulatory agent that could enhance vaccine efficacy and ensure broad-spectrum protection against HP-PRRSV in pigs.

With the proposal of the 2030 Agenda for Sustainable Development, the Chinese medicine extraction technology has been innovatively improved to prioritize low energy consumption, sustainability, and minimized organic solvent utilization. Forsythia suspensa (FS) possesses favorable pharmacological properties and is extensively utilized in traditional Chinese medicine. However, due to the limitations of the composition and extraction methods, its potential has not been fully developed. Thus, a combination of ultrasound-assisted extraction (UAE), enzyme-assisted extraction (EAE), and β-cyclodextrin extraction (β-CDE) was employed to isolate and purify rutin, phillyrin, and forsythoside A from FS. The results demonstrated that the efficiency of extracting enzymatic and ultrasound assisted β-cyclodextrin extraction (EUA-β-CDE) was highly influenced by the temperature and duration of hydrolysis, as well as the duration of the extraction process. According to the results of the single-factor experiment, Box-Behnken design (BBD) in Response surface method (RSM) was used to optimize the experimental parameters to achieve the maximum comprehensive evaluation value (CEV) value. The EUA-β-CDE compared with other extraction methods, has good extraction effect and low energy consumption by high performance liquid chromatography (HPLC), scanning electron microscopy (SEM), calculation of power consumption and CO2 emission The EUA-β-CDE compared with other extraction methods, has good extraction effect and low energy consumption by HPLC, SEM, calculation of power consumption and CO2 emission. Then, the structural characteristics of EUA-β-CDE of FS extract had significant interaction with β-CD by Fourier infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). In addition, EUA-β-CDE extract has good antioxidant and anti-inflammatory activities. The establishment of EUA-β-CDE of FS provides a new idea for the development and application of other sustainable extraction methods of traditional Chinese medicine.

ObjectiveTo evaluate and explore the feasibility of using quality control indicators for nutritional therapy in critically ill patients as quality evaluation criteria.MethodsThis study focused on intensive care unit (ICU) critically ill patients and conducted a cross-sectional investigation of nutritional therapy quality control indicators (the proportion of patients with application of enteral nutrition pump, nutritional risk assessment rate, the proportion of patients start enteral nutrition within 48 hours, and caloric and protein target achievement rate on 7th day) in 13 hospitals in Jilin Province. After training according to the critical patients nutrition related guidelines and the latest literatures, a second cross-sectional investigation was conducted. Then, analyze the improvement of quality control indicators of the nutritional therapy before and after the training, thus evaluating the feasibility of using these quality control indicators as nutritional therapy quality evaluation criteria in critical patients.Results(1) A total of 631 patients were included before and after training, with a data acquisition rate of 97.3% for enteral nutrition pumps usage and complete data collection for the remaining nutritional risk assessment rate, start enteral nutrition proportion of patients within 48 h, and caloric and protein target achievement rate on 7th day. (2) The nutritional risk assessment rate before and after training was 88.2% vs. 94.8%, with a P-value of 0.003. The proportion of patients start enteral nutrition within 48 h before and after training was 65.1% vs. 75.4%, with a P-value of 0.039; and protein target achievement rate on 7th day before and after training was 64.6% vs. 79.6%, with a p-value of 0.015. These five indicators as quality evaluation criteria are relevant to the current developments in nutritional therapy and consistent with the national conditions of China. The proportion of patients with application of enteral nutrition pump before and after training was 70.1% vs. 79.4%, with a p-value of 0.065, and the caloric target achievement rate on 7th day before and after training was 73.4% vs. 83.9%, with a p-value of 0.062, and there was no statistical difference between the two groups.ConclusionThe five quality control indicators for nutritional therapy in critically ill patients are clinically feasible and can be used as quality evaluation criteria for nutritional therapy in critically ill patients.

China has the largest pig herd in the world which accounts for more than 50% of the global pig population. Over the past three decades, the porcine reproductive and respiratory syndrome virus (PRRSV) has caused significant economic loss to the Chinese swine industry. Currently, the prevalent PRRSV strains in the field are extremely complicated, and the NADC30-like strains, NADC34-like strains, and novel recombinant viruses have become a great concern to PRRS control in China. In this study, a novel NADC30-like PRRSV, named GS2022, was isolated from the lung of a dead pig collected from a farm that experienced a PRRS outbreak. The complete genome of GS2022 shares the highest identity with the NADC30 strain and contains a discontinuous deletion of 131 aa in nsp2. Novel deletion and insertion have been identified in ORF7 and 3’UTR. Recombination analysis revealed that the GS2022 is a potential recombinant of NADC30-like and JXA1-like strains. Both inter-lineage and intra-lineage recombination events were predicted to be involved in the generation of the GS2022. An infectious cDNA clone of GS2022 was assembled to generate the isogenic GS2022 (rGS2022). The growth kinetics of rGS2022 were almost identical to those of GS2022. The pathogenicity of the GS2022 and rGS2022 was evaluated using a nursery piglet model. In the infection groups, the piglets exhibited mild clinical symptoms, including short periods of fever and respiratory diseases. Both gross lesions and histopathological lesions were observed in the lungs and lymph nodes of the infected piglets. Therefore, we reported a novel recombinant NADC30-like PRRSV strain with moderate pathogenicity in piglets. These results provide new information on the genomic characteristics and pathogenicity of the NADC30-like PRRSV in China.

The intrinsic resistance of MRSA coupled with biofilm antibiotic tolerance challenges the antibiotic treatment of MRSA biofilm infections. Phytochemical-based nanoplatform is a promising emerging approach for treatment of biofilm infection. However, their therapeutic efficacy was restricted by the low drug loading capacity and lack of selectivity. Herein, we constructed a surface charge adaptive phytochemical-based nanoparticle with high isoliquiritigenin (ISL) loading content for effective treatment of MRSA biofilm. A dimeric ISL prodrug (ISL-G2) bearing a lipase responsive ester bond was synthesized, and then encapsulated into the amphiphilic quaternized oligochitosan. The obtained ISL-G2 loaded NPs possessed positively charged surface, which allowed cis-aconityl-d-tyrosine (CA-Tyr) binding via electrostatic interaction to obtain ISL-G2@TMDCOS-Tyr NPs. The NPs maintained their negatively charged surface, thus prolonging the blood circulation time. In response to low pH in the biofilms, the fast removal of CA-Tyr led to a shift in their surface charge from negative to positive, which enhanced the accumulation and penetration of NPs in the biofilms. Sequentially, the pH-triggered release of d-tyrosine dispersed the biofilm and lipase-triggered released of ISL effectively kill biofilm MRSA. An in vivo study was performed on a MRSA biofilm infected wound model. This phytochemical-based system led to ∼2 log CFU (>99 %) reduction of biofilm MRSA as compared to untreated wound (P < 0.001) with negligible biotoxicity in mice. This phytochemical dimer nanoplatform shows great potential for long-term treatment of resistant bacterial infections.

Abstract Anxiety-associated symptoms following acute stress usually become extinct gradually within a period of time. However, the mechanisms underlying how individuals cope with stress to achieve the extinction of anxiety are not clear. Here we show that acute restraint stress causes an increase in the activity of GABAergic neurons in the CeA (GABACeA) in male mice, resulting in anxiety-like behaviors within 12 hours; meanwhile, elevated GABACeA neuronal CX3CL1 secretion via MST4 (mammalian sterile-20-like kinase 4)-NF-κB-CX3CL1 signaling consequently activates microglia in the CeA. Activated microglia in turn inhibit GABACeA neuronal activity via the engulfment of their dendritic spines, ultimately leading to the extinction of anxiety-like behaviors induced by restraint stress. These findings reveal a dynamic molecular and cellular mechanism in which microglia drive a negative feedback to inhibit GABACeA neuronal activity, thus facilitating maintenance of brain homeostasis in response to acute stress.

Objective: Although the parietal cortex is related to consciousness, the dorsolateral prefrontal and primary motor cortices are the usual targets for repetitive transcranial magnetic stimulation (rTMS) for prolonged disorders of consciousness (pDoC). Herein, we applied parietal rTMS to patients with pDoC, to verify its neurobehavioral effects and explore a new potential rTMS target. Materials and methods: Twenty-six patients with pDoC were assigned to a rTMS or sham group. The rTMS group received 10 sessions of parietal rTMS; the sham group received 10 sessions of sham stimulation. The Coma Recovery Scale-Revised (CRS-R) and event-related potential (ERP) were collected before and after the 10 sessions or sham sessions. Results: After the 10 sessions, the rTMS group showed: a significant CRS-R score increase; ERP appearance of a P300 waveform and significantly increased Fz amplitudes; increased potentials on topographic mapping, especially in the left prefrontal cortex; and an increase in delta and theta band powers at Fz, Cz, and Pz. The sham group did not show such changes in CRS-R score or ERP results statistically. Conclusion: Parietal rTMS shows promise as a novel intervention in the recovery of consciousness in pDoC. It showed neurobehavioral enhancement of residual brain function and may promote frontal activity by enhancing frontal–parietal connections. The parietal cortex may thus be an alternative for rTMS therapy protocols.

ObjectiveThis study recalculates the carbon emissions of urban and rural residents in China, analyzing the dynamic evolution trends of urban and rural carbon emissions. It explores the spatial spillover effects centered around the inequality in carbon emissions between urban and rural areas.MethodsThe study calculates the carbon emissions of urban and rural residents in each province based on the IPCC method. Non-parametric kernel density estimation is employed to depict the dynamic evolution characteristics of national, urban, and rural carbon emissions. The Theil Index is used to measure the disparities in urban and rural carbon emissions in major strategic regions, further applying the Theil Index to evaluate the inequality of urban and rural carbon emissions across provinces. This helps identify the driving factors affecting the inequality of urban and rural carbon emissions and their spatio-temporal effects.FindingCarbon emissions from urban and rural residents in China present a divergent development pattern. Urban emissions have increased, with inter-provincial disparities widening; rural emissions tend to stabilize, with slight growth in inter-provincial gaps. The overall inequality of carbon emissions in various regions of China experiences a three-phase journey of rise, decline, and stabilization. Urban inequality first increases then decreases, while rural inequality gradually lessens, showing clear regional and urban-rural differences. Market and government factors significantly impact the inequality of urban and rural carbon emissions. The development of the digital economy aids in reducing inequality and generates significant spatial spillover effects. The relationship between economic development level and carbon emission inequality is U-shaped. Industrial structure optimization can reduce urban-rural inequality, but its spatial spillover effect is not significant. Government intervention has limited effects, while environmental regulations may increase inequality. Opening up to the outside world helps reduce inequality, and the impact of population density is complex.

Abstract Small peptide formulas versus standard polymeric formulas for enteral nutrition in critically ill patients with acute gastrointestinal injury (AGI) have been a topic of debate. A systematic review and meta-analysis were conducted to compare their clinical and nutritional outcomes. Relevant studies from January 1980 to June 2022 were searched in PubMed, Cochrane, and Embase databases. Randomized controlled trials involving AGI grade I-IV patients were included, while children, non-AGI patients, and non-critically ill patients were excluded. Results indicated no significant difference in all-cause mortality. Patients receiving small peptide formulas showed higher daily protein intake, greater albumin growth, and higher prealbumin levels. They also had shorter lengths of stay in the intensive care unit and hospital. Conversely, patients receiving standard polymeric formulas had a higher daily calorie intake. In conclusion, the choice of formula may not affect mortality in critically ill patients with AGI. Small peptide formulas were more conducive to increase daily protein intake, decrease intensive care unit and hospital length of stay. Further large-scale randomized controlled trials evaluating the effects of these two nutritional formulas on clinical and nutritional outcomes in critically ill patients with AGI are needed to confirm these results.

Abstract Obesity is a recognized risk factor for heart failure. People with similar weights may have different metabolic health. Notably, insulin resistance is a hallmark of obesity and a feature of heart failure. We aimed to evaluate the effects of obesity and metabolic health status on subclinical left cardiac function. We also investigated whether insulin resistance (TyG index) plays a role in BMI-linked subclinical left cardiac dysfunction. The study involved 403 volunteers. Hierarchical multiple regression models were used to assess associations between obesity, metabolic health, and overall subclinical left cardiac function. Mediating analysis was used to explore the role of the TyG index in the association between BMI and left cardiac function. Finally, ROC analysis was performed to explore the predictive value of the TyG index in subclinical left cardiac dysfunction. The correlation analysis showed that metabolic unhealth increased the risk of subclinical left ventricular (LV) dysfunction; obesity was associated with an increased risk of global left cardiac dysfunction regardless of metabolic health status. The TyG index mediated 25% of the associations between BMI and Left atrial (LA) functional parameters. ROC analysis exhibited that the TyG index can be used as a predictor of LA dysfunction (AUC = 0.63), and the optimal cut-off point for the TyG index is 9.33. Even a “non-obese metabolically unhealthy” is a detrimental state of early LV function; obesity remains a major risk factor for global subclinical left cardiac dysfunction. Using the TyG index could allow early identification of individuals at high risk of subclinical left cardiac dysfunction. Registration number: ChiCTR2200057991; Date of registration: 2022-03-25. URL: http://www.chictr.org.cn/showproj.aspx?proj=162316 .

Abstract Background Porcine reproductive and respiratory syndrome (PRRS) remains one of the most important infectious diseases for the pig industry. A novel small-scale transmission experiment was designed to assess whether the WUR0000125 (WUR for Wageningen University and Research) PRRS resilience single nucleotide polymorphism (SNP) confers lower susceptibility and infectivity to pigs under natural porcine reproductive and respiratory syndrome virus (PRRSV-2) transmission. Methods Commercial full- and half-sib piglets (n = 164) were assigned as either Inoculation, Shedder, or Contact pigs. Pigs were grouped according to their relatedness structure and WUR genotype, with R− and R+ referring to pigs with zero and one copy of the dominant WUR resilience allele, respectively. Barcoding of the PRRSV-2 strain (SD09-200) was applied to track pig genotype-specific transmission. Blood and nasal swab samples were collected and concentrations of PRRSV-2 were determined by quantitative (q)-PCR and cell culture and expressed in units of median tissue culture infectious dose (TCID50). The Log10TCID50 at each sampling event, derived infection status, and area under the curve (AUC) were response variables in linear and generalized linear mixed models to infer WUR genotype differences in Contact pig susceptibility and Shedder pig infectivity. Results All Shedder and Contact pigs, except one, became infected through natural transmission. There was no significant (p > 0.05) effect of Contact pig genotype on any virus measures that would indicate WUR genotype differences in susceptibility. Contact pigs tended to have higher serum AUC (p = 0.017) and log10TCID50 (p = 0.034) when infected by an R+ shedder, potentially due to more infectious R+ shedders at the early stages of the transmission trial. However, no significant Shedder genotype effect was found in serum (p = 0.274) or nasal secretion (p = 0.951) that would indicate genotype differences in infectivity. Conclusions The novel design demonstrated that it is possible to estimate genotype effects on Shedder pig infectivity and Contact pig susceptibility that are not confounded by family effects. The study, however, provided no supportive evidence that genetic selection on WUR genotype would affect PRRSV-2 transmission. The results of this study need to be independently validated in a larger trial using different PRRSV strains before dismissing the effects of the WUR marker or the previously detected GBP5 gene on PRRSV transmission.

Abstract Background Islet transplantation is used therapeutically in a minority of patients with type 1 diabetes (T1D). However, successful outcomes are hampered by early islet β-cell loss caused by immune rejection and autoimmunity. Recent studies have demonstrated that mesenchymal stromal cells can enhance islet function both in vitro and in vivo by secreting ligands that activate islet G-protein coupled receptors (GPCRs). Stromal cell-derived factor 1 (SDF-1) is an MSC-secreted GPCR ligand, whereas the suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of STAT3-activating cytokines. Here, we determined whether improvement in islet function mediated by exogenous SDF-1 is impaired by SOCS3 in experimental models of T1D. Methods Isolated islets were cultured for 48 h with SDF-1. Cytokine-induced apoptosis was measured immediately. Islets from Socs3 −/− mice were pre-cultured with exogenous SDF-1 and transplanted underneath the kidney capsule of C57BL/6 mice with streptozotocin-induced diabetes. Blood glucose levels were monitored for 28 days. AMD3100, an antagonist of the SDF-1 ligand CXCR4, was administered subcutaneously to islet transplanted mice to inhibit CXCR4 before and after transplantation. Results SDF-1 protected islet cells from cytokine-induced apoptosis in vitro. SOCS3-knockout (KO) islets pretreated with SDF-1 were effective in reducing blood glucose in non-obese diabetic mice in vivo. We found that SDF-1 elicits localized immunosuppression in transplanted SOCS3-KO islets. Immunomodulation was observed when SOCS-KO islets were preconditioned with SDF-1. Gene expression and flow cytometric analyses revealed significantly decreased immune cell infiltration, inflammatory cytokines, and concomitant increases in FOXP3+ regulatory T cells, alternatively activated M2 macrophages, and dendritic cell phenotypes. Administration of AMD3100 impaired the SDF-1-mediated improvement in SOCS3-KO islet function and local immune suppression. Conclusion SDF-1 improves the function of islet grafts in autoimmune diabetes through regulation by CXCR4; however, the presence of SOCS3 reverses the protective effect of SDF-1 on islet grafts. These data reveal a molecular pathway that can elicit localized immunosuppression and delay graft destruction in transplanted islets.

This study evaluated the effects of active dry yeast (ADY) supplementation and supplementation strategies on ruminal fermentation, bacterial community, blood metabolites, and growth performance in young dairy goats. Sixty young female Guanzhong dairy goats of similar age (4.00 ± 0.50 months) and BW (19.65 ± 0.41 kg) were randomly divided into 3 groups (n = 20): (1) basal diet group (CON); (2) basal diet continuously supplemented with 3.0 g/goat per day commercial ADY (a proprietary strain of Saccharomyces cerevisiae with 5.0 × 109 cfu/g) group (CSY); (3) basal diet with intermittently supplemented ADY group (ISY; 5 d supplementation with ADY at 4.5 g/goat per day following 5 d of no supplementation). The experiment lasted 67 d with the first 7 d as an adaptive period. Rumen fluid and blood samples were collected bi-weekly. Data were analyzed using the MIXED procedure combined with the SLICE option in SAS. Specific orthogonal contrasts of ADY vs. CON and CSY vs. ISY were also analyzed. During the experimental period, ADY supplementation resulted in greater DMI (P = 0.03), ruminal acetate proportion (P

Polycystic ovarian syndrome (PCOS) is a metabolic, reproductive, and psychological disorder affecting 6–20% of reproductive women worldwide. However, there is still no cure for PCOS, and current treatments primarily alleviate its symptoms due to a poor understanding of its etiology. Compelling evidence suggests that hyperandrogenism is not just a primary feature of PCOS. Instead, it may be a causative factor for this condition. Thus, figuring out the mechanisms of androgen synthesis, conversion, and metabolism is relatively important. Traditionally, studies of androgen excess have largely focused on classical androgen, but in recent years, adrenal-derived 11-oxygenated androgen has also garnered interest. Herein, this Review aims to investigate the origins of androgen excess, androgen synthesis, how androgen receptor (AR) signaling mediates adverse PCOS traits, and the role of 11-oxygenated androgen in the pathophysiology of PCOS. In addition, it provides therapeutic strategies targeting hyperandrogenism in PCOS.

Coronavirus disease 2019 (COVID-19) cases in China has grown rapidly after adjustment of the dynamic zero-COVID-19 strategy. However, how different vaccination states affect symptoms, severity and post COVID conditions was unclear. Here, we used an online questionnaire to investigate the infection status of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among 11,897 participants, with 55.55% positive and 28.42% negative. The common COVID-19 symptoms were fatigue (73.31%), cough (70.02%), fever (65.25%) and overall soreness (58.64%); self-reported asymptomatic infection accounted for 0.7% of participants. The persistent symptoms at 1 month after infection included fatigue (48.7%), drowsiness (34.3%), cough (30.1%), decreased exercise ability (23.1%) and pharyngeal discomfort (19.4%), which was reduced by more than 200% at 2 months. Participants with complications such as chronic obstructive pulmonary disease, respiratory diseases, diabetes, hypertension, etc. have a higher proportion of hospitalization and longer recovery time (p 39.1 °C), chills, diarrhea and ageusia/anosmia, respectively (p

Abstract With the expansion of the aging population, age-associated sarcopenia (AAS) has become a severe clinical disease of the elderly and a key challenge for healthy aging. Regrettably, no approved therapies currently exist for treating AAS. In this study, clinical-grade human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were administrated to two classic mouse models (SAMP8 mice and D-galactose-induced aging mice), and their effects on skeletal muscle mass and function were investigated by behavioral tests, immunostaining, and western blotting. Core data results showed that hUC-MSCs significantly restored skeletal muscle strength and performance in both mouse models via mechanisms including raising the expression of crucial extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging. For the first time, the study comprehensively evaluates and demonstrates the preclinical efficacy of clinical-grade hUC-MSCs for AAS in two mouse models, which not only provides a novel model for AAS, but also highlights a promising strategy to improve and treat AAS and other age-associated muscle diseases. This study comprehensively evaluates the preclinical efficacy of clinical-grade hUC-MSCs in treating age-associated sarcopenia (AAS), and demonstrates that hUC-MSCs restore skeletal muscle strength and performance in two AAS mouse models via raising the expression of extracellular matrix proteins, activating satellite cells, enhancing autophagy, and impeding cellular aging, which highlights a promising strategy for AAS and other age-associated muscle diseases.

This paper investigates the impact of e-commerce participation on household development resilience using a sample of 1229 households in the Shandong and Shaanxi provinces of China in 2022. It constructs the developmental resilience index of farm households from three dimensions of economy, society and culture using the entropy method, and establishes a counterfactual framework using the Propensity Score Matching (PSM) method. The results suggest that participation in e-commerce has a significant and positive impact on farming household development resilience. The PSM method estimates that participation in e-commerce increases the developmental resilience of farming households by 9.63% compared to non-participation, with economic, social, and cultural resilience increasing by 9.29%, 9.84%, and 9.92%, respectively. The robustness test results confirm the findings. Further analysis reveals that participation in e-commerce enhances farm household development resilience through three mechanisms: improving economic efficiency, network relationship linkage, and risk appetite. Heterogeneity analysis shows that the impact of e-commerce participation on household development resilience varies among farmers with different endowment constraints. In particular, farmers with more years of education and cooperative members benefit more from e-commerce participation, especially live and platform e-commerce.

Grain size is a quantitative trait with a complex genetic mechanism, characterized by the combination of grain length (GL), grain width (GW), length to width ration (LWR), and grain thickness (GT). In this study, we conducted quantitative trait loci (QTL) analysis to investigate the genetic basis of grain size using BC1F2 and BC1F2:3 populations derived from two indica lines, Guangzhan 63-4S (GZ63-4S) and TGMS29 (core germplasm number W240). A total of twenty-four QTLs for grain size were identified, among which, three QTLs (qGW1, qGW7, and qGW12) controlling GL and two QTLs (qGW5 and qGL9) controlling GW were validated and subsequently fine mapped to regions ranging from 128 kb to 624 kb. Scanning electron microscopic (SEM) analysis and expression analysis revealed that qGW7 influences cell expansion, while qGL9 affects cell division. Conversely, qGW1, qGW5, and qGW12 promoted both cell division and expansion. Furthermore, negative correlations were observed between grain yield and quality for both qGW7 and qGW12. Nevertheless, qGW5 exhibited the potential to enhance quality without compromising yield. Importantly, we identified two promising QTLs, qGW1 and qGL9, which simultaneously improved both grain yield and quality. In summary, our results laid the foundation for cloning these five QTLs and provided valuable resources for breeding rice varieties with high yield and superior quality.

ABSTRACT African swine fever virus (ASFV) is a complex nucleocytoplasmic, large DNA virus that infects both domestic pigs and wild boar, but little is known about the process of genomic replication. The E301R protein (pE301R) from ASFV was previously predicted as a proliferating cell nuclear antigen (PCNA)-like protein through clamping DNA polymerase to the DNA duplex, but its exact structure and functions remain uncharacterized. Here, the crystal structure of pE301R revealed that it is composed of structurally similar head and tail domains and shares significant structural similarities to the DNA polymerase processivity factors, including sliding clamp and eukaryotic PCNA. More specifically, we demonstrated that pE301R exhibited multiple oligomeric states (with dimers and tetramers dominant), and the tetramers are consistent with the ring-shaped homotetramers in a head-to-tail manner generated by crystal packing. We also showed that pE301R interacted with the ASFV genome and viral DNA polymerase O174L. Furthermore, knockdown of E301R by specific small interfering RNAs (siRNAs) significantly decreased the virus genomic replication. Interestingly, the downregulation of PCNA by siRNAs significantly decreased the cell viability, whereas the inhibitory effect was reversed by pE301R overexpression. Notably, we demonstrated that overexpression of PCNA partially restored ASFV replication upon transfection of siRNAs targeting E301R. More importantly, T2 amino alcohol, a PCNA-specific inhibitor, markedly inhibited ASFV replication at the stage of viral genome replication. Taken together, we revealed that pE301R functions as a sliding clamp in ASFV genomic replication and can be used as a potential antiviral target. IMPORTANCE Sliding clamp is a highly conserved protein in the evolution of prokaryotic and eukaryotic cells. The sliding clamp is required for genomic replication as a critical co-factor of DNA polymerases. However, the sliding clamp analogs in viruses remain largely unknown. We found that the ASFV E301R protein (pE301R) exhibited a sliding clamp-like structure and similar functions during ASFV replication. Interestingly, pE301R is assembled into a unique ring-shaped homotetramer distinct from sliding clamps or proliferating cell nuclear antigens (PCNAs) from other species. Notably, the E301R gene is required for viral life cycle, but the pE301R function can be partially restored by the porcine PCNA. This study not only highlights the functional role of the ASFV pE301R as a viral sliding clamp analog, but also facilitates the dissection of the complex replication mechanism of ASFV, which provides novel clues for developing antivirals against ASF.